This is a renewal application for a Midcareer Investigator Award in Patient-Oriented Research (K24). By relieving me of substantial clinical and administrative responsibilities, the K24 has allowed me to increase the level of my involvement in research aimed at improving the efficacy and accessibility of treatments for opioid and cocaine dependence, expand my research into the international arena, and increase my mentoring of beginning investigators. Current studies are investigating 1) contracting and behavioral activation therapy for methadone maintained patients with persistent depressive symptoms, 2) the pharmacogenetics of disulfiram response to cocaine during buprenorphine maintenance treatment, 3) buprenorphine maintenance in primary care settings, and 4) buprenorphine and naltrexone for treating opioid dependence in Malaysia and Iran, predominantly Muslim countries facing extreme problems of opioid dependence and the emergence of HIV. The international studies are two of the major projects planned for the initial years of the proposed K24 and described more fully in this application. Both are randomized, double blind comparisons of buprenorphine and naltrexone;the 3-cell study in Malaysia includes a placebo (drug counseling only) group. Both provide opportunities for training and mentoring beginning drug abuse researchers and developing a drug abuse clinical research infrastructure that will support future research and dissemination of evidence-based treatments in these countries. My mentoring of beginning investigators occurs in the context of the clinical trials. During the current grant period, I have served as research mentor for four beginning investigators who have succeeded in developing independent areas of research and obtaining external support for their research, and I am currently mentoring 8 investigators. My clinical research and mentoring activities are facilitated by the extensive clinical research, teaching and clinical programs in drug abuse at Yale and by the development of several international HIV and drug abuse clinical research training programs.